Researchers developed biohybrid microrobots that deliver bacteria and piezoelectric nanoparticles via capsules for localized colorectal cancer treatment and immune activation.
(Nanowerk Spotlight) Colorectal cancer is among the most commonly diagnosed cancers worldwide and remains a leading cause of cancer-related death. While early-stage tumors can often be removed surgically, patients with advanced disease, particularly those with metastases, face limited treatment options and poor survival rates.
Conventional therapies such as chemotherapy, targeted agents, and immunotherapy have shown mixed results. Many patients develop resistance or experience systemic side effects that reduce treatment tolerance. Tumor heterogeneity and the unique environment of the colon complicate efforts to deliver effective therapy where it is most needed.
Oral drug delivery offers an attractive alternative. By targeting the colon directly, oral treatments can deliver drugs to the tumor site while reducing the exposure of healthy tissues to toxic agents. This can limit adverse effects and improve patient adherence. However, the digestive tract poses substantial challenges. Drugs must survive the highly acidic stomach environment and resist degradation by digestive enzymes.
Reaching the tumor requires crossing the dense mucus layer that protects the intestinal lining. Even then, the tumor microenvironment itself—often poorly vascularized and rich in immunosuppressive factors—limits drug absorption and immune activity.
Efforts to overcome these obstacles have led to new therapeutic concepts. One approach involves using bacteria naturally present in the gut. Certain species can thrive in the low-oxygen conditions of tumors, penetrate mucus, and produce gases that help break down physical barriers. These bacteria can also influence the immune system, promoting the activity of immune cells that attack tumors.
A second, parallel line of research has explored the use of catalytic nanoparticles that generate reactive molecules when exposed to ultrasound. These particles can damage cancer cells directly and alter the chemical composition of the tumor environment to make it more hospitable to immune responses.
A recent study from researchers at Tianjin University integrates these two approaches into a single oral treatment strategy. Their work (Advanced Materials, “Biohybrid Microrobot Enteric-Coated Microcapsule for Oral
Treatment of Colorectal Cancer”) introduces a biohybrid microrobot system that combines engineered bacteria with ultrasound-responsive nanoparticles. This system is encapsulated in acid-resistant microcapsules, allowing the components to survive the upper digestive tract and release their therapeutic payload directly in the colon.
The microrobot core is based on Enterobacter aerogenes (EA), a bacterial species commonly found in the human intestine. EA naturally colonizes the colon and is well suited to the conditions typically found in colorectal tumors: low oxygen, high acidity, and a thick mucus barrier. EA is also capable of producing hydrogen and carbon dioxide through fermentation. These gases not only disrupt the mucus barrier but may also facilitate deeper penetration of the bacterial cells into the tumor.
To enhance these properties, the researchers coated EA with nanoparticles of barium titanate (BaTiO₃, or BTO), a piezoelectric material that responds to ultrasound. Under ultrasound stimulation, BTO generates electrical charges that catalyze redox reactions. These reactions produce reactive oxygen species—highly reactive molecules that can damage tumor cells and trigger immunogenic cell death. BTO also promotes the oxidation of lactic acid, a metabolite produced in large amounts by tumors that suppresses immune responses. By depleting lactic acid, the treatment aims to reprogram the tumor environment to support immune activation.
The resulting composite, referred to as EA@BTO, is designed to retain the metabolic and mobility properties of EA while adding catalytic functionality. To ensure that these microrobots reach the colon intact, the team developed enteric microcapsules using a 3D-printed structure. The capsules consist of a gelatin-based core surrounded by a calcium alginate shell, forming a protective barrier against stomach acid. Testing in simulated digestive fluids confirmed that the capsules remain intact in acidic conditions and begin to dissolve only when they reach the more neutral pH of the intestine. Once released, the microrobots are free to interact with the tumor environment.
Laboratory tests demonstrated that EA@BTO retains key functional properties. The bacteria remained viable after encapsulation and release. They were able to migrate through synthetic mucus barriers and selectively accumulate in 3D tumor spheroid models. BTO loading did not eliminate EA’s gas production, although it caused a modest reduction.
In parallel, the team confirmed that the BTO nanoparticles retained their catalytic activity. When exposed to ultrasound, EA@BTO generated superoxide and hydroxyl radicals, as well as carbon monoxide from carbon dioxide and other oxidation products. These reactions were not observed in control groups without ultrasound, indicating that catalytic activation is tightly controlled.
Cell culture experiments showed that EA@BTO reduced the viability of colorectal cancer cells. The effect was enhanced by ultrasound exposure, which increased the production of reactive molecules. The treatment caused mitochondrial damage, DNA fragmentation, and signs of apoptosis, suggesting multiple mechanisms of cell death. Importantly, the same treatment had a lesser effect on normal intestinal epithelial cells, likely reflecting differences in their metabolic activity and resistance to stress.
The researchers also examined how the treatment influenced immune activation. Using a co-culture system that included dendritic cells (which play a central role in antigen presentation), they observed increased expression of surface markers associated with immune maturation. Macrophages exposed to treated tumor cells showed a shift toward the M1 phenotype, associated with pro-inflammatory and tumor-suppressive functions. CD8+ cytotoxic T cells, isolated from mouse spleens and exposed to the treatment, also showed increased activation. These results suggest that EA@BTO helps stimulate both the innate and adaptive arms of the immune system.
In mouse models of colorectal cancer, EA@BTO capsules administered orally were able to reach the colon and accumulate at tumor sites. Fluorescence imaging confirmed that the capsules protected the bacteria during transit and degraded predictably in the intestine. Mice receiving EA@BTO in combination with ultrasound showed significantly reduced tumor burden compared to control groups, including those treated with bacteria alone. Mice in this group also maintained their weight, a common proxy for general health in cancer models.
A survival study further supported these results. Mice treated with EA@BTO and ultrasound survived significantly longer than untreated controls, with a majority surviving to the end of the 60-day study period. Importantly, the treatment also had effects beyond the primary tumor. In a model of liver metastasis, mice receiving EA@BTO and ultrasound for their primary colorectal tumors exhibited suppressed growth of secondary tumors in the liver. This suggests that the immune activation induced by local treatment may have systemic effects.
Several features of the microrobot system help explain its performance. Unlike nanoscale drug carriers, which rely on passive diffusion, the micrometer-scale bacteria can actively migrate, produce gas, and proliferate in the tumor. This allows them to overcome physical barriers and sustain therapeutic action at the site.
The encapsulation system ensures that these benefits are delivered specifically to the colon, avoiding degradation and off-target effects. Ultrasound provides an external trigger that activates the BTO particles only after they reach their destination, minimizing unintended reactions elsewhere in the body.
This work demonstrates the feasibility of combining microbial and catalytic therapies in a single, orally administered platform. By integrating bacterial targeting, ultrasound-triggered catalysis, and metabolic reprogramming, the system addresses multiple barriers to effective colorectal cancer treatment.
The approach remains in the preclinical stage, and further studies will be needed to optimize dosing, timing, and safety. However, the results suggest a promising path toward non-invasive, localized, and multi-mechanistic cancer therapy.
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